Synergistic combination comprising roflumilast and an anticholinergic agent selected from ipratropium, oxitropium and tiotropium salts for the treatment of respiratory diseases

ABSTRACT

The invention relates to the administration of roflumilast and an anticholinergic agent selected from the group of an ipratropium, oxitropium or tiotropium salt for the treatment of respiratory diseases.

FIELD OF APPLICATION OF THE INVENTION

The Invention relates to the combination of certain known activecompounds for therapeutic purposes. The substances used in thecombination according to the invention are a known active compound fromthe PDE inhibitor class and active compounds from the anticholinergicagent class.

Prior Art

International patent applications WO02/069945 and WO03/011274 generallydescribe the combination of a compound from the class of PDE4 inhibitorswith a compound from the class of anticholinegic agents for thetreatment of respiratory tract disorders. International Patentapplication WO02/096463 describes an inhaled combination of a selectivePDE4 inhibitor and an anticholinergic agent, with the proviso that theanticholinergic agent is not a tiotropium salt. International patentapplication WO02/096423 describes a combination of therapeutic agentsuseful in the treatment of obstructive airways and other inflammatorydiseases comprising (I) a PDE4 inhibitor that is therapeuticallyeffective in the treatment of said diseases when administered byinhalation; together with (II) an anticholinergic agent comprising amember selected from the group consisting of tiotropium and derivativesthereof that is therapeutically effective in the treatment of saiddiseases when administered by inhalation. In the U.S. patent applicationNo. US2002/0052312 a method for the treatment of chronic obstructivepulmonary disease is described comprising administering orally to apatient in need of such treatment a therapeutically effective amount ofa muscarinic receptor antagonist in combination with a therapeuticallyeffective amount of at least one other therapeutic agent selected fromthe group consisting of: β2-agonist, antitussive, corticosteroid,decongestant, histamine H1 antagonist, dopamine antagonist, leukotrieneantagonist, 5-lipoxygenase inhibitor, phosphodiesterase IV inhibitor,VLA-4 antagonist and theophylline.

SUMMARY OF THE INVENTION

The invention relates to pharmaceutical compositions and methods forpreventing or reducing the onset of symptoms of respiratory diseases, ortreating or reducing the severity of respiratory diseases. In particularit relates to compositions and methods for treating respiratory diseasesmediated by phosphodiesterase 4 (PDE4) by administering a PDE4 inhibitortogether with another pharmaceutically active agent, which affectspulmonary function. In this connection, it is the object of the presentinvention to make available a certain respiratory tract therapeutic,which fulfills the following conditions:

-   -   Pronounced antiinflammatory action    -   Distinct bronchorelaxation and -dilatation    -   Good bioavailability    -   Minor side effects    -   Good suitability for long-term therapy    -   Favorable influence on bronchial hyperreactivity

It has now been found that the combined use of the PDE4 inhibitorroflumilast and an anticholinergic agent selected from the group ofipratropium, oxitropium and tiotropium salts outstandingly fulfills theabovementioned conditions, in particular in view of the fact that thecombination of the compounds acts synergistically, i.e. exhibits agreater than additive effect.

Accordingly, the invention relates in a first aspect to a method forpreventing or reducing the onset of symptoms of a respiratory disease,or treating or reducing the severity of a respiratory disease byadministering to a patient in need thereof by inhalation an effectiveamount of roflumilast and an anticholinergic agent selected from thegroup of ipratropium, oxitropium and tiotropium salts.

The invention also relates to a pharmaceutical composition suited foradministration by inhalation for preventing or reducing the onset ofsymptoms of a respiratory disease, or treating or reducing the severityof a respiratory disease, comprising an effective amount of roflumilast,an effective amount of an anticholinergic agent selected from the groupof ipratropium, oxitropium and tiotropium salts, together withpharmaceutically acceptable excipients and/or carriers.

The invention additionally relates to a method for preparing acomposition which is effective for preventing or reducing the onset ofsymptoms of a respiratory disease, or treating or reducing the severityof a respiratory disease, which method comprises mixing an effectiveamount of roflumilast and an anticholinergic agent selected from thegroup of ipratropium, oxitropium and tiotropium salts withpharmaceutically acceptable excipients and/or carriers.

The invention furthermore relates to the use of a combination ofroflumilast and an anticholinergic agent selected from the group ofipratropium, oxitropium and tiotropium salts for the preparation of apharmaceutical composition for preventing or reducing the onset ofsymptoms of a respiratory disease, or treating or reducing the severityof a respiratory disease.

DETAILED DESCRIPTION OF THE INVENTION

The combination therapy which is the subject matter of this inventioncomprises administering roflumilast with an anticholinergic agentselected from the group of ipratropium, oxitropium and tiotropium saltsto prevent the onset of a respiratory disease event or to treat anexisting condition. The two compounds are administered intranasal (e.g.in form of a nasal spray) or by inhalation together in a single dosageform; or they are administered intranasal (e.g. in form of a nasalspray) or by inhalation in two different dosage forms. They may beadministered at the same time. Or they may be administered both close intime or remotely, such as where one active compound is administered inthe morning and the second active compound is administered in theevening.

The combination may be used prophylactic or after the onset of symptomshas occurred. In some instances the combination may be used to preventthe progression of a respiratory disease or to arrest the decline of afunction such as lung function.

The invention thus relates to the combined use of roflumilast and ananticholinergic agent selected from the group of ipratropium, oxitropiumor tiotropium salts, preferably ipratropium bromide, oxitropium bromideor tiotropium bromide in preventing the symptoms of, or treating arespiratory disease.

In the sense of the invention, the term “roflumilast” is understood toinclude the pharmaceutically acceptable salts and the N-oxide ofROFLUMILAST, which can likewise be used according to the invention.

ROFLUMILAST is the International nonproprietary name (INN) for3-cyclopropylmethoxy-4-difluoromethoxy-N-(3,5-dichloropyrid-4-yl)benzamide[structure of formula (1.1)]. The preparation of3-cyclopropylmethoxy-4-difluoromethoxy-N-3,5-dichloropyrid-4-yl)benzamide,its pharmaceutically acceptable salts and its N-oxide[3-cyclopropylmethoxy-4-difluoromethoxy-N-(3,5-dichloro-1-oxypyrid-4-yl)-benzamide;structure of formula (1.2)] as well as the use of these compounds asphosphodiesterase (PDE) 4 inhibitors is described in WO95/01338.

Suitable pharmaceutically acceptable salts of3-cyclopropylmethoxy-4-difluoromethoxy-N-(3,5-dichloropyrid-4-yl)benzamide(ROFLUMILAST) are in particular water-soluble and water-insoluble acidaddition salts with acids such as, for example, hydrochloric acid,hydrobromic acid, phosphoric acid, nitric acid, sulfuric acid, aceticacid, citric acid, D-gluconic acid, benzoic acid,2-(4-hydroxybenzoyl)-benzoic acid, butyric acid, sulfosalicylic acid,maleic acid, lauric acid, malic acid, fumaric acid, succinic acid,oxalic acid, tartaric acid, embonic acid, stearic acid, toluenesulfonicacid, methanesulfonic acid or 1-hydroxy-2-naphthoic acid, the acidsbeing employed in salt preparation—depending on whether it is a mono- orpolybasic acid and depending on which salt is desired—in an equimolarquantitative ratio or one differing therefrom.

Anticholinergic agents suitable for use in the invention areipratropium, oxitropium or tiotropium salts.

An ipratropium salt (see DE1670142) has the structure of formula (1.3)

wherein X is a pharmaceutically acceptable anion.An oxitropium salt (see DE1795818) has the structure of formula (1.4)

wherein X is a pharmaceutically acceptable anion.

A tiotropium salt (see EP 418716) has the structure of formula (1.5):

wherein X is a pharmaceutically acceptable anion.

Examples of suitable salt forms of ipratropium, oxitropium andtiotropium are fluoride, F⁻; chloride, Cl⁻; bromide, Br⁻; iodide, I⁻;methanesulfonate, CH₃S(=O)₂O⁻; ethanesulfonate, CH₃CH₂S(═O)₂O⁻;methylsulfate, CH₃OS(═O)₂O⁻; benzene sulfonate C₅H₅S(═O)O⁻; andpara-toluenesulfonate, 4CH₃-C₆H₅S(═O)2O⁻. The bromide salt form ispreferred.

Preferred combinations for use in the invention include:

-   -   roflumilast and an ipratropium salt, particularly ipratropium        bromide    -   roflumilast and an oxitropium salt, particularly oxitropium        bromide    -   roflumilast and a tiotropium salt, particularly tiotropium        bromide or tiotropium bromide monohydrate

It Is understood that the active compounds and their pharmaceuticallyacceptable salts mentioned can also be present, for example, in the formof their pharmaceutically acceptable solvates, in particular in the formof their hydrates. Of particular importance in this connection istiotropium bromide in form of its crystalline monohydrate as disclosedand described in detail in WO02/30928. The preparation of crystallinewater-free tiotropium bromide is described in WO03/000265. Analternative process for the preparation of tiotropium bromide isdescribed in WO02/051840.

Respiratory diseases which may be mentioned are in particular allergen-and inflammation-induced bronchial disorders (bronchitis, obstructivebronchitis, spastic bronchitis, allergic bronchitis, allergic asthma,bronchial asthma, COPD), which can be treated by the combinationaccording to the invention also in the sense of a long-term therapy (ifdesired with appropriate adjustment of the dose of the individualcomponents to the needs at the time, for example needs subject toseasonally related variations). The combination is particularly usefulin the treatment of COPD.

“Combined use” or “combination” within the meaning of the presentinvention is to be understood as meaning that the individual componentscan be administered simultaneously (in the form of a combinationmedicament—fixed combination), or in succession (from separate packunits—free combination), close in time or remote in time, in any orderwhatever. As an example, one active compound could be taken in themorning and one later in the day. Or in another scenario, one activecompound could be taken twice daily and the other once daily, either atthe same time as one of the twice-a-day dosing occurred, or separately.Preferred is the once daily administration of the fixed combination. Incase of administration in succession of the two active compounds it ispreferred that the anticholinergic agent is administered first androflumilast thereafter.

“Combined use” or “combination” within the meaning of the presentinvention is particularly to be understood as meaning that the twoactive compounds act together in a synergistic manner.

“Use” in accordance with the invention is to be understood to meanadministration of the active compounds by inhalation (via mouth or vianose) or intranasal administration. As suitable administration forms forinhalation may be mentioned inhalation powders, propellant-containingaerosols and propellant-free inhalation solutions and/or suspensions. Assuitable intranasal administration form may be mentioned, for example, anasal spray or liquids for nasal administration (e.g. nose drops).

Thus, the invention contemplates, for example, either co-administeringboth active compounds in one delivery form such as an inhaler, which isputting both active compounds in the same inhaler, or alternativelyputting the both active compounds in two different inhalers. Or, as afurther alternative, administering one active compound intranasally, forexample in form of a nasal spray, and the other active compound byinhalation.

The selective PDE4 inhibitors and the anticholinergic agents of thepresent invention may be conveniently delivered in the form of a drypowder inhaler or an aerosol spray presentation from a pressurizedcontainer, pump, spray, atomizer (preferably an atomizer usingelectrodynamics to produce a fine mist or nebulizer, with or without theuse of a suitable propellant, e.g. dichlorodifluoromethane,trichlorofluoromethane, dichlorotetrafluoroethane, a hydrofluoroalkanesuch as 1,1,2,2-tetrafluoroethane (HFA 134A [trade mark]) or,1,1,1,2,3,3,3-heptafluorapropane (HFA 227EA [trade mark]), carbon diox-

metered dose. The pressurized container, pump, spray, or nebulizer maycontain a solution or suspension of the selective PDE4 inhibitor and/orthe anticholinergic agent, e.g. using a mixture of ethanol (optionallyaqueous ethanol) or a suitable agent for dispersing, solubilizing orextending release and the propellant as the solvent, which mayadditionally contain a lubricant, e.g. sorbitan trioleate. Capsules,blisters and cartridges (made, for example, from gelatin or HMPC) foruse in an inhaler or insulator may be formulated to contain a powder mixof the selective PDE4 inhibitor and/or the anticholinergic agent of theinvention, a suitable powder base, such as lactose or starch and aperformance modifier such as I-leucine, mannitol or magnesium stearate.

Prior to use in a dry powder formulation for inhalation selective PDE4inhibitors and the anticholinergic agents of the invention will bemicronised to a size suitable for delivery by inhalation (typicallyconsidered as less than 5 microns). Micronisation could be achieved by arange of methods, for example spiral jet milling, fluid bed jet millingor use of supercritical fluid crystallization.

A suitable solution formulation for use in an atomizer usingelectrohydrodynamics to produce a fine-mist may contain from 1 μg to 10mg of an anticholinergic agent of the invention and the actuation volumemay vary from 1 to 100 μl. A typical formulation may comprise ananticholinergic agent of the invention, propylene glycol, sterile water,ethanol and sodium chloride.

Aerosol or dry powder formulations are preferably arranged so that eachmetered dose or “puff” contains from 1 to 4000 μg of an anticholinergicagent of the invention for delivery to the patient. The overall dailydose with an aerosol will be in the range from 1 μg to 20 mg which maybe administered in a single dose or, alternatively, in divided dosesthroughout the day.

Typical formulations for intranasal administration include thosementioned above for inhalation and further include non-pressurizedformulations in form of a solution or suspension in an inert vehiclesuch as water optionally in combination with conventional excipientssuch as buffers, anti-microbials, tonicity modifying agents andviscosity modifying agents, which may be administered by a nasal pump.

With respect to tiotropium bromide or tiotropium bromide monohydratesuitable tiotropium-containing powdery preparations for inhalativeadministration are disclosed in the International applicationsWO02/30389 and WO03/084509. In the International application WO02/098874inhalation capsules (Inhalettes) containing the active agent tiotropiumin the form of a powder preparation are disclosed. Propellant-freeinhalation formulations of tiotropium bromide or tiotropium bromidemonohydrate are disclosed in the International applications WO02/36104and WO02/36591. Aerosol formulations, free

disclosed in the International application WO03/084519. Methods for theproduction of micronized crystalline tiotropium bromide are disclosed inWO03/078429.

For the above-mentioned prophylactic and therapeutic uses the dosagesadministered will, of course vary with the first and second activecompound employed, the treatment desired and the disorder indicated.

The active compounds are dosed in an order of magnitude customary forthe individual dose, it more likely being possible, on account of theindividual actions, which are mutually positively influencing andreinforcing, to reduce the respective doses on the combinedadministration of the active compounds compared with the norm.

For inhalation, ipratropium bromide is administered in a dose ofpreferably 1 to 3 mg per day by once, twice, three or four times dailyadministration; oxitropium bromide is administered in a dose ofpreferably 0.2to 0.6 mg per day by once, twice or three times dailyadministration; tiotropium bromide monohydrate is administered in a doseof 10 to 25 μg, preferably 22.5 μg per day by once daily administration.

For inhalation,3-cyclopropylmethoxy-4-difluoromethoxy-N-(3,5-dichloropyrid-4-yl)benzamide(ROFLUMILAST) is administered in a dose of 100 μg to 1000 μg, preferably250 μg to 500 μg per day, preferably by once daily administration.

For intranasal administration,3-cyclopropylmethoxy-4-difluoromethoxy-N-(3,5dichloropyrid-4-yl)benzamide(ROFLUMILAST) is administered in a dose of 100 μg to 1000 μg, preferably250 μg to 500 μg per day, preferably by once daily administration.

PREPARATION EXAMPLES

There follows a description of several Examples showing preparation ofpharmaceutical compositions containing a combination of active compoundsin accordance with the present invention. These examples are intended tofurther illustrate the combinations of active compounds of the presentinvention, pharmaceutical compositions containing them and processes inaccordance with which said pharmaceutical compositions may be readilyprepared by a person skilled in the art. The person skilled in the artwill be aware of many other suitable processes and pharmaceuticallyacceptable carriers that are also available, as well as acceptablevariations in the procedures and ingredients described below.

Example 1 Dry Powder Inhaler (Mono Dose System Based on Capsule forInhalation)

2.50 g micronized ROFLUMILAST, 0.225 g micronized tiotropium bromidemonohydrate and 47.3 g lactose monohydrate are mixed in a turbula mixerin two steps. The blend is screened (0.71 mm sieve) to break up anyagglomerates and, subsequently, transferred into the container of aplanetary mixer. After adding additional 200.0 g lactose monohydrate andmixing, 25 mg of the blend are filled into hard gelatin capsules size #3using a capsule filling machine. The capsules can be administered with acommercially available inhaler, e.g., the Cyclohaler®. One capsulecontains 250 μg of ROFLUMILAST and 22.5 μg of tiotropium bromidemonohydrate.

Example 2 Dry Powder Inhaler (Multi Dose System)

1.50 g of micronized tiotropium bromide monohydrate and 14.5 g ofdeagglomerated lactose monohydrate are screened (0.5 mm sieve) and mixedin a turbula mixer until homogenous. The blend obtained is screened (0.5mm sieve) and filled into a stainless steel container together with 6.67g of screened ROFLUMILAST (0.5 mm sieve) and 227.4 g of deagglomeratedlactose monohydrate and blended in a turbula mixer for a predeterminedtime. Another 250.0 g of deagglomerated lactose monohydrate are added tothe blend. The powders are blended in a turbula mixer until homogenous.1.2 g of the blend are then filled into the reservoir of a multi dosepowder inhaler. After fully assembling, the powder inhaler is pouchedinto a moisture protective aluminum foil.

Such dry powder inhaler may contain 120 individual doses of 7.5 mgpowder each containing 100 μg of ROFLUMILAST and 22.5 μg of tiotropiumbromide monohydrate.

Pharmacology

Inhibition of Methacholine-Induced Bronchoconstriction in Guinea Pigs byROFLUMILAST in combination with tiotropium-bromide

Objective

To assess the inhibitory effect of tiotropium-bromide, ROFLUMILAST, andthe combination of both compounds on methacholine-inducedbronchoconstriction in anaesthetized, mechanically ventilated guineapigs.

Animals

Male Dunkin Hartley guinea pigs; body weight 350-450 g when performingthe experiments.

Experimental Procedure

75 min before methacholine-induced bronchospasm (at −75 min) animalswere anaesthetized with urethane i.p. (1.2 g/kg). At −55 min for I.v.injections the right jugular vein and for ventilation the trachea wascannulated. At −45 min NaCl 0.9% or tiotropium-bromide was administeredI.v. (1 μg/kg). At −30 min lactose (10 mg/kg) or ROFLUMILAST (4 mg/kg)mixed with lactose was administered intratracheally by a dry powderaerolizer. At −10 min pancuronium-bromide (1.5 mg/kg) was administeredI.v. to abolish spontaneous breathing. Animals were mechanicallyventilated with 60 breath/min and a tidal volume of 7 ml/kg. Dynamiclung compliance (COM) and airway conductance (CON) were calculated withthe help of a computer system from airflow and ventilation pressuresignals. At t=0 min methacholine was administered i.v. (60 μg/kg) toinduce bronchoconstriction.

Analysis of Lung Physiology Data

COM and CON were determined up to 120 s after methacholine-inducedbronchospasm. AUCs for 0 to 120s were determined. Inhibition wascalculated based on the AUC data. Data are shown as mean ±SEM. Resultswere taken to be significant if p<0.05 versus placebo (ANOVA andDunnett's multiple comparison test)

Results

Injection of methacholine induced an immediate bronchoconstrictioncharacterized by a decrease of COM and CON; maximum at 20 s (FIG. 1 andFIG. 2).

Pretreatment with ROFLUMILAST had no significant effect onmethacholine-induced bronchospasm (FIG. 1-4, COM—1.6% CON 5.6%).

Pretreatment with tiotropium-bromide had no significant effect onmethacholine-induced bronchospasm (FIG. 1-4 COM 12%, CON 5.9%).

Combination of both treatments led to an unexpected synergisticsignificant (p<0.01) inhibition of methacholine-induced COM decrease(FIG. 1 and 3, COM 41%) and CON decrease (FIG. 2 and 4, CON 25% p<0.05).

CONCLUSION

Whereas ROFLUMILAST and tiotropium-bromide alone had no influence onmethacholine-induced bronchospasm in aneasthetized and mechanicallyventilated guinea pigs, combination of both active compounds showed anunexpected synergistic inhibition.

DESCRIPTION OF THE FIGURES

FIG. 1: Methacholine induced compliance decrease in guinea pigs

FIG. 2: Methacholine induced conductance decrease in guinea pigs

FIG. 3: AUC Compliance 0-120 s

FIG. 4: AUC Conductance 0-120 s

1. Pharmaceutical composition suited for administration by inhalation,which comprises roflumilast and an anticholinergic agent selected fromthe group of ipratropium, oxitropium and tiotopium salts together withpharmaceutically acceptable excipients and/or carriers in a fixed orfree combination.
 2. Pharmaceutical composition according to claim 1,which is a fixed combination.
 3. Pharmaceutical composition according toclaim 1, which is a free combination.
 4. A pharmaceutical compositionaccording to claim 1, 2 or 3 wherein the anticholinergic agent istiotropium bromide or tiotropium bromide monohydrate.
 5. Apharmaceutical composition according to claim 1, 2 or 3 wherein theanticholinergic agent is ipratropium bromide.
 6. A pharmaceuticalcomposition according to claim 1, 2 or 3, wherein the anticholinergicagent is oxitropium bromide.
 7. A pharmaceutical composition accordingto any of claims 1 to 6, wherein roflumilast represents3-cyclopropylmethoxy-4-difluoromethoxy-N-(3,5-dichloropyrid-4-yl)benzamide.8. A pharmaceutical composition according to any of claims 1 to 6,wherein roflumilast represents3-cyclopropylmethoxy-4-difluoromethoxy-N-(3,5-dichloro-1-oxypyrid-4-yl)benzamide.9. Method for preventing or reducing the onset of symptoms of arespiratory disease, or treating or reducing the severity of arespiratory disease by administering to a patient in need thereof byinhalation an effective amount of roflumilast and an anticholinergicagent selected from the group of ipratropium, oxitropium and tiotropiumsalts, either in a single combined form, separately, or separately andsequentially, where the sequential administration is close in time orremote in time.
 10. Method according to claim 9, wherein theanticholinergic agent is tiotropium bromide or tiotropium bromidemonohydrate.
 11. Method according to claim 9, wherein theanticholinergic agent is ipratropium bromide.
 12. Method according toclaim 9, wherein the


13. Method according to any of claims 9 to 12, wherein roflumilastrepresents3-cyclopropylmethoxy-4-difluoromethoxy-N-(3,5-dichloropyrid-4-yl)benzamide.14. Method according to any of claims 9 to 12, wherein roflumilastrepresents3-cyclopropylmethoxy-4-difluoromethoxy-N-(3,5-dichloro-1-oxypyrid-4-yl)benzamide.15. Method according to any of claims 9 to 14, wherein the respiratorydisease is COPD.
 16. Use of a combination of roflumilast and ananticholinergic agent selected from the group of ipratropium, oxitropiumand tiotropium salts for the preparation of a pharmaceutical compositionfor preventing or reducing the onset of symptoms of a respiratorydisease, or treating or reducing the severity of a respiratory disease.17. Use according to claim 16, wherein the anticholinergic agent istiotropium bromide or tiotropium bromide monohydrate.
 18. Use accordingto claim 16, wherein the anticholinergic agent is ipratropium bromide.19. Use according to claim 16, wherein the anticholinergic agent isoxitropium bromide.
 20. Use according to any of claims 16 to 19, whereinroflumilast represents3-cyclopropylmethoxy-4-difluoromethoxy-N-(3,5-dichloropyrid-4-yl)benzamide.21. Use according to any of claims 16 to 19, wherein roflumilastrepresents3-cyclopropylmethoxy-4-difluoromethoxy-N-3,5-dichloro-1-oxypyrid-4-yl)benzamide.22. Use according to any of claims 16 to 21, wherein the respiratorydisease is COPD.